Over the past quarter century, the concept of "therapeutic vaccines" has broadened from the initial, narrow meaning of a immunization against a microbial pathogen to the current, broad meaning of any treatment that can stimulate a beneficial immune response. As a result, scientists and physicians are now trying to develop "vaccines" against such esoteric targets as tumors and drugs of addiction. The latter category includes vaccines against nicotine. The logic of a nicotine vaccine is that circulating anti- nicotine antibodies will intercept nicotine in the blood before it reaches the brain where its physiologic target resides. Already, pre-clinical and clinical trial data support the concept that nicotine vaccines can reduce the physiologic effects of smoking and reduce the likelihood of regaining an addiction to nicotine after smoking cessation. In parallel with the development of nicotine vaccines, there have been advances in the delivery vehicles for vaccines. Among these advances is the recognition that vaccines delivered as small particles ("nanoparticles" ranging from 40 to 100 billionths of a meter in diameter) and vaccines delivered by viruses are more efficacious than vaccines delivered by soluble proteins. A central concept in this application is that viruses, and in particular, adenoviruses, represent an especially effective form of nanoparticle vaccines due to their size (80 billionths of a meter) and their ability to interact with the cell surface as part of their infection cycle. This application seeks to combine the efficacy of adenovirus-based vaccines with the importance of nicotine as a target and will test the hypothesis that direct covalent conjugation of nicotine to the adenovirus caspid will result in a highly effective vaccine that is capable of generating therapeutically relevant levels of anti-nicotine antibodies. PUBLIC HEALTH RELEVANCE: Project Narrative. Recent studies suggest that vaccines are more effective if they are delivered as tiny particles (nanoparticles) instead of soluble proteins. The present study will test whether adenovirus, a nanoparticle that is approximately 80 billionths of a meter wide, can be used to create a new, even more effective class of nanoparticle vaccines. Studies will focus on a vaccine against nicotine, which may help smokers to quit smoking.